title: Stochastic modelling of tumorigenesis in p53 deficient mice.
abstract: Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the 'multigate' model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten. The multigate model predicts a relationship between the time pattern of tumour occurrence and tumour genotype that should be experimentally testable. Stochastic modelling may help to distinguish 'gatekeeper' and 'caretaker' genes in other tumorigenic pathays.
authors.affiliation: Department of Radiation Oncology, University of Glasgow, CRC Beatson Laboratories, UK.
authors.forename: J H
authors.initials: JH
authors.lastname: Mao
authors.forename: K A
authors.initials: KA
authors.lastname: Lindsay
authors.forename: A
authors.initials: A
authors.lastname: Balmain
authors.forename: T E
authors.initials: TE
authors.lastname: Wheldon
mesh_terms: D000818:Animals; D017353:Gene Deletion; D016158:Genes, p53; D008433:Mathematics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D009374:Neoplasms, Experimental / Q000235:genetics*; D014411:Neoplastic Stem Cells / Q000502:physiology; D013269:Stochastic Processes